Phenotypes change in Lyme disease


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3A025657-AB95-47F2-931B-B9841D546B67Changing phenotypes complicate Western Medicine diagnosis and treatment of Lyme disease!

A phenotype results from the expression of an organism’s genes as well as the influence of environmental factors and the interactions between the two.

Because the physical characters (phenotypes) of the infections associated with Lyme disease are constantly changing it is not possible to have precise testing and treatment of these organisms through traditional pathology.

Persister organisms with their changed phenotypes are the most significant reason that Western medicine cannot reliably test & treat Lyme disease:

Lyme disease caused by Borrelia burgdorferi  and co-infections is the most common vector borne disease in the United States and Europe.1,2 The current treatment for Lyme disease is a 2-4 week antibiotic monotherapy with doxycycline, amoxicillin or cefuroxime.3 While this treatment is effective for  Lyme disease patients, if treated in the 6weeks following infection, about 10%-20% of patients still have persisting symptoms such as fatigue, muscular pain, and neurological impairment even six months after the treatment,1 a collection of symptoms called Post Treatment Lyme Disease Syndrome (PTLDS).4 While the cause of PTLDS remains unclear and controversial, several hypotheses have been proposed to explain PTLDS, including host response to continued presence of bacterial debris,5 autoimmunity,6 co-infections,7 and presence of bacterial persisters not killed by the current Lyme antibiotics.7Consistent with the persisting organisms not killed by current antibiotics, experiments in various animal models such as mice, dogs and monkeys have shownB. burgdorferi could still be detected after treatment with different Lyme antibiotics though viable organisms could not be cultured.8,9,10 In vitro studies also demonstrated that B. burgdorferi could develop antibiotic tolerant persisters.11 Although persister mechanisms have been reported in the model organism E. coli,12 the mechanisms of B. burgdorferi persisters remain unknown.
Our findings not only shed new light on the mechanisms of B. burgdorferi persisters but also have practical applications. For example, the upregulated genes identified in B. burgdorferi persisters may not only serve as targets for developing new drugs for more effective treatment but also antigens for developing diagnostic tests for persistent Lyme disease, and finally for developing therapeutic vaccines for improved treatment. Future studies are needed to address these possibilities for more effective control of Lyme disease.
Dr Horowitz summed it up:-
Major universities are finally taking an interest in persister bacteria and their role in contributing to chronic symptoms in patients with Lyme disease. Dr Ying Zhang and researchers from Johns Hopkins University just published on Borrelia persisters in Emerging Microbes and Infections where they identified the gene expression profile for Bb persisters that survived antibiotic treatment with doxycycline and amoxicillin. They found differences in transporter genes, bacterial envelope protein coding genes, DNA repair related genes, bacterial chemotaxis genes, bacterial secretion genes, and genes encoding proteases. Comparison of the pathways of the doxycycline persisters and amoxicillin persisters revealed that they share several common features where some genes were up regulated and some down regulated. “These gene expression changes may play important roles in facilitating survival of B. burgdorferi persisters under antibiotic stress…and the upregulated genes identified in B. burgdorferi persisters may not only serve as targets for developing new drugs for more effective treatment but also antigens for developing diagnostic tests for persistent Lyme disease, and finally for developing therapeutic vaccines for improved treatment”. The MSIDS map identifies up to 16 different reasons why patients may stay ill after classical treatment for Lyme disease. Persistent infection with borrelia species and co-infections certainly plays a large role in chronic illness, but we must also treat associated inflammation, autoimmune reactions, detoxify internal and external biotoxins, repair the damage caused by free radicals and oxidative stress which damage mitochondria, nerves, brain cells and internal organs, while balancing cytokines, hormones, and the microbiome. Once all of the associated factors on the 16 point MSIDS map have been adequately addressed, the vast majority of my patients improve. A large thanks goes out to the Global Lyme Alliance for their support of this research, and to Dr Zhang and his colleagues at Johns Hopkins for continuing to search for answers for this debilitating illness.

The tick is one carrier of the disease:


How is it possible that an epidemic of tick-borne diseases could be spreading without getting the proper attention from Western Medicine and politicians ? How could patients throughout the world continue to be desperate for help?

Sixty years ago, Nobel Prize-winning scientist Joshua Lederberg first described a biological mystery. He showed how bacteria could lose the cell walls that define their shapes, potentially becoming less visible to the immune system, only to later revert back to their original form and regain their full infectious potential.

Lyme disease epidemic:


 Persister mechanisms in Borrelia burgdorferi: implications for improved intervention

Jie Feng, Wanliang Shi, Shuo Zhang and Ying Zhang
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
Citation: Emerging Microbes & Infections (2015) 4, e51; doi:10.1038/emi.2015.51
Published online 19 August 2015
Received 11 July 2015; Revised 1 August 2015; Accepted 5 August 2015
Click on Dr Klinghardt’s name at the top of this page
for his scientific approach to Lyme disease.

The Patients:


This disease can spread throughout the body from the site of the initial bite, and even within 24 hours can invade the central nervous system.



Lyme Symptoms:

The most common Lyme related inflammation causes:

optic neuritis: inflammation of the optic nerve

iritis: inflammation in the anterior chamber of the eye

Meningococcal disease is an uncommon, unpredictable, and serious disease that can include meningitis (infection of the lining of the brain and spinal cord) and/or sepsis (blood infection). Even with appropriate treatment, roughly 1 in 10 people who contract meningococcal meningitis or sepsis die within 24 to 48 hours from the start of symptoms, and those who survive may face severe consequences, such as loss of arms or legs, brain damage, or hearing loss.1,2

encephalitis: inflammation in the sac, surrounding the brain and in the brain tissue itself: inflammation of the brain and spinal cord

carditis: inflammation of the heart

Lyme arthritis: inflammation of the joints

multiple sclerosis: numbness in body, tingling, pin pricks

Burning/stabbing sensations in the body, burning in the feet

Weakness or paralysis of the limbs

Tremors or unexplained shaking: stroke

Poor balance, dizziness, difficulty walking

Increased motion sickness, wooziness

Lightheadedness, fainting

Encephalopathy (cognitive impairment from brain involvement)

Academic or vocational decline

Difficulty multitasking

Difficulty with organisation and planning

Auditory processing problems

Word finding problems

Slowed speed of processing

Head Face Neck

Facial paralysis (like Bell’s Palsy)

Tingling of nose, cheek or face

Stiff neck

Sore throat swollen glands

Heightened allergic sensitivities

Twitching of facial/ other muscles

Jaw pain/stiffness

Change in smell, taste

Skin: Benign tumour-like nodules

Erythema Migrans (rash)

Respiratory/ Circulatory:

Difficulty breathing

Night sweats or unexplained chills

Heart palpitations

Diminished exercise tolerance

Heart block, murmur

Chest pain or rib soreness


Decreased hearing

Ringing or buzzing in ears

Sound sensitivity

Pain in ears


Cognitive Symptoms:

Forgetfulness, memory loss (short or long term)

Poor school or work performance

Attention deficit problems, distractibility

Confusion, difficulty thinking

Difficulty with concentration, reading, spelling

Disorientation: getting or feeling lost

Psychiatric symptoms:

Mood swings, irritability, agitation and anxiety

Depression, anxiety, personality changes, malaise


Aggressive behavior impulsiveness

Suicidal thoughts, rare cases of suicide

Over emotional reactions crying easily

Disturbed sleep, too much, too little, difficulty falling asleep or staying asleep

Suspiciousness, paranoia, hallucinations

Feeling as though you are losing your mind

Obsessive compulsive behavior

Bi-polar disorder/ manic behavior

Schizophrenia like state including hallucinations

Lyme disease (LD) is the world’s leading tick borne infection caused by the spirochete,Borrelia burgdorferi (Bb). This infection is a global health concern and is associated with numerous cardiologic, dermatologic, rheumatologic neurologic, and psychiatric manifestations (Bratton et al., 2008). Only a few epidemiologic studies have evaluated the frequency of antibodies to Bb in psychiatric patients; one study found only 1/517 (0.2%) of all adult psychiatric patients had Lyme titer seropositivity (Nadelman et al., 1997) and the other larger study found that 322/926 (35%) of psychiatric inpatients had seropositivity to antibodies to Bb (Hajek et al., 2002).
If you would like a copy of the Hajek paper please contact us through the ‘Free testing’ tag at the top of this page,

Musculoskeletal System:

Lyme Arthritis

Joint pain swelling or stiffness

Shifting joint pain: Fibromyalgia

Muscle pain or cramps

Poor muscle coordination, loss of reflexes

Loss of muscle tone, muscle weakness

General Well Being

Profound fatigue


Chronic fatigue


Upset stomach (nausea, vomiting)

Irritable bladder

Unexplained weight loss or gain, loss of appetite, anorexia


The Doctors: 


To understand the answer to this dilemma, you need to understand the intricacies of Lyme disease and the conditions controlling doctors and health authorities.

Treating Lyme Disease:

Doctors have been forced to enter the battle against Lyme Disease. Many have already been forced out of medicine, lost their licences, or been forced to undergo medical monitoring, because they have not followed guidelines sanctioned by medical licensing boards.

They have spent hundreds of thousands of dollars in legal fees to uphold their licences.

Antibiotics for Lyme Disease:

Consequently, many states, including Rhode Island and California, have formally recognised that it is not professional medical misconduct to use longer term antibiotics to treat Lyme disease.

The ineffectual testing and ineffective paradigms that modern medicine offers provide no satisfactory answers.

Without a paradigm shift, the present approach to this epidemic ensure that the suffering will continue.

Dr Horowitz believes that the identification of MSIDS, multiple systemic infections disease syndrome, may prove to be the missing link to end this war once and for all.

One year it was the clue that led to the identification of a strain Babesia microti, a malaria like illness that could explain the fevers, chills, and day & night sweats and that account for some of their resistant symptoms.

Once treated, some patients using wheel chairs could stand and walk.

Next was the discovery of cat scratch disease symptoms, or Bartonella, which could explain their resistant neurological symptoms, such as treatment-resistant neuropathy or encephalopathy.

Next was the uncovering of Mycoplasma fermentans, the organism suspected in Gulf War syndrome and possibly a contributor to some patient’s  ALS-type symptoms.

More recently we have been able to link the presence of heavy metals, such as mercury, lead, arsenic, cadmium, and aluminium, with patient’s overlapping symptomatology.

These can be treated with IV glutathione and oral chelation regimens such as DMSA to detoxify  treatment resistant patients.

The results have been astounding. You need to know that your symptoms are not only real and identifiable, but they are treatable.

Treating Chronic Lyme:

Many people who have received treatment for Lyme disease do not feel well either during treatment or once the courses of antibiotics are completed.

For these patients, the Horowitz sixteen point differential diagnostic map is the best way to determine if they are suffering from MSIDS (multiple systemic infection disease syndrome).

Patients with complex chronic illnesses, no matter which diagnosis they receive, often have simultaneous bacterial, parasitic, viral and fungal causes for their illness.

Many times they also have associated immune dysfunction, large environmental toxic loads, hormonal dysfunctions, mitochondrial dysfunction, allergies, sleep disorders, or underlying  psychological dysfunction.

The history of Medicine:

Medicine is a continuously changing and expanding field.

It is said that almost half of what is learnt at Medical School will usually be proven to be wrong every five to ten years. But along the way to modern medicine, some medical pioneers have been dismissed or even attacked for what others believed were their heretical ideas.

Semmelweiss discovered that washing his hands before delivering a child prevented puerperal sepsis that kills women after giving birth. When he shared his findings with colleagues he was ridiculed. As patients abandoned his colleagues and begged to deliver in his clinic, he was ostracized by his medical society and driven out of medicine. He was committed to an asylum, where ironically, he died of septicemia after being severely beaten by his guards.

Dr Louis Pasteur who was ridiculed and it was years  before his germ theory causing illness was proven to be correct.

Australian doctors Barry Marshall and Robin Warren discovered Heliobacter  pylori in the stomachs of patients with gastritis and stomach ulcers. They also proposed that treatment with antibiotics rather than stomach removal, were best for ulcer patients. Their discovery was ignored for 20 years, until proof led to Nobel prizes in medicine .

Many of these pioneers pushed the boundaries until the paradigm of that specific disease process was transformed. Are things different today? Have we learnt to listen to those challenging  the medical establishment? Certainly not with respect to Lyme Disease and associated tick-borne disorders.

History of Lyme Disease:

In the mid 1970s, when portrait painter Polly Murray first noticed an outbreak of what had been called “juvenile rheumatoid arthritis” in the town of Lyme, Connecticut, that had affected her and her children from decades earlier.

Dr Alan Steere, a rheumatologist at Yale University, was called in to investigate the epidemic, as were researchers from the National Institutes of Health (NIH) and Rocky Mountain Labs.

Dr Willy Burgdorfer, a researcher at Rocky Mountain Labs, identified a microscopic spirochete, a spiral shaped bacteria that resembles the one that causes syphilis. This was eventually identified as the causative  agent of the newly identified disease, and the spirochete was named Borrelia burgdorferi (Bb) after Dr Burgdofer’s discovery, and the related disease  was caused Lyme, after its initial outbreak in the town of Lyme, Connecticut.

By 1977 Dr. Steere was reporting a whole host of specific and often bizarre signs of this new disease, including fever, fatigue, headache, migratory joint pains, as well as multiple cardiovascular and neurological abnormalities.

If a Lyme disease patient presents with 35 different symptoms, the established paradigm would be to try and explain these complaints according to the accepted medical model: one primary diagnosis.

If the doctor could not find a single aetiology, or cause, for your symptoms, it must be because it is psychological in nature, and you are crazy.

Or the answer maybe elusive because the symptoms can’t be understood in the HMO-dictated fifteen minute time frame.

Getting to the source of chronic illness:

The Horowitz Lyme-MSIDS Questionnaire:

This essential questionnaire  is based on one  developed by Dr joseph Burrascano when he started treating Lyme disease patients.  You can use the following questionnaire to determine the probability of a Lyme MSIDS  diagnosis for yourself.

All of the points on the list in section 1 are  symptoms that can be seen with lyme disease.  They are not specific to lyme disease in and of themselves, and can be found in many other illnesses. However the advantage that  can be perceived by looking at all of the symptoms simultaneously helps the clinician reach a probability as to whether the patient may suffer from Lyme disease and associated tick-borne disorders.

At the same time this list can also be used to identify simultaneous overlapping disease states, so that the true source of the patient suffering is discovered.

These multifactorial causes of illness are often at the heart of most chronic disease states, and this led Dr Horowitz to create the MSIDS model.

Sections 2 and 3 of the questionnaire represent those signs and symptoms complexes most associated with Lyme and MSIDS, which Dr Horowitz has compiled after examining hundreds of our patients charts over the last decade.

Section 4 is based on two of the four questions in the healthy days core module used by the CDC to track population trends nationally and identify healthcare disparities, and it helps us identify the frequency of physical and mental health problems in the preceding month.

Talk to your doctor about the results of this questionnaire. Depending on your score you may want to follow up with blood tests for lyme disease or electrotherapy testing with Hope Australia (0412 994 001).

Do not just rely on the CDC criteria of using  Eliza in a two tiered testing protocol as this is not sensitive enough to confirm the diagnosis. You can use this questionnaire as the starting point of the decision-making detective work that will lead you to the proper diagnosis.

Remember, Lyme disease is a clinical diagnosis  and the blood tests only help to confirm your clinical suspicion.

Answer the following questions as honestly as possible stop  think about how you have been feeling over the previous month and how often you have been bothered by any of the following problems. Score the occurrence of each symptom on the following scale none,  mild,  moderate,  severe.

Lyme Disease Symptoms:

Section 1: Symptom frequency score: circle your score number:

0 None 1 Mild 2 Moderate 3 Severe

1.  unexplained fevers, sweats, chills, or flushing  0 1 2 3

2.  unexplained weight change ; loss or gain0 1 2 3

3.  fatigue ,  tiredness 0 1 2 3

4.  unexplained hair loss0 1 2 3

5. swollen glands 0 1 2 3

6.  sore throat 0 1 2 3

7.  testicular or pelvic pain0 1 2 3

8.   unexplained menstrual irregularity0 1 2 3

9.  unexplained breastmilk production ; breast pain 0 1 2 3

10.  irritable bladder or bladder dysfunction 0 1 2 3

11.   sexual dysfunction Or loss of libido 0 1 2 3

12.  upset stomach 0 1 2 3

13. change in bowel function. .(constipation.or diarrhea)  0 1 2 3

14. chest pain or rib soreness 0 1 2 3

15.   shortness of breath or cough 0 1 2 3

16. Heart palpitations ,  pulse skips, Heart block  0 1 2 3

17.  history of a heart murmur or valve prolapse 0 1 2 3

18.  joint pain or swelling 0 1  2 3

19.  stiffness of the neck  or back 0 1 2 3

20.  muscle pain or cramps 0 1 2 3

21.  twitching of the face or other muscles 0 1 2 3

22.  headaches  0 1 2 3

23.  neck cracks or neck stiffness 0 1 2 3

24. tingling,   numbness, burning for stabbing sensations 0 1 2 3

25. facial paralysis Bell’s palsy 0 1 2 3

26.   eyes vision  double  blurry 0 1 2 3

27.  ears Hearing buzzing  ringing  ear  pain 0 1 2 3

28. Increased  motion  sickness vertigo 0 1 2 3

29.  light-headedness  poor balance  difficulty walking  0 1 2 3

30. tremors  0 1 2 3

31.  confusion  Difficulty thinking 0 1 2 3

32. difficulty with concentration or reading 0 1 2 3

33.  forgetfulness  poor short  term  memory0 1 2 3

34.  disorientation  getting lost  going to the wrong places  0 1 2 3

35. difficulty with speech or writing 0 1 2 3

36.  mood swings   irritability  depression 0 1 2 3

37. disturbed sleep  too much too little  early awakening  0 1 2 3

38.  exaggerated symptoms or worse hangover from alcohol  0 1 2 3

Add up your totals from each of the four columns . This is your first score.

Section 2 :  Most common Lyme symptoms score:

If you rated a three for each of the following in section 1,  give yourself five additional points :


Forgetfulness poor short-term memory

joint pain or swelling

tingling numbness burning or stabbing sensations

disturbed sleep  too much too little early awakening


Section 3  lyme incidence score

Now please circle the points for each of the following statements you can agree with:

1. You have had a tick bite with no rash or fluke symptoms 3 points

2. You have had a tick bite, an erythema migrans, or an undefined rash, followed by flu like symptoms 5 points

3.  You live in what is considered a Lyme-endemic area 2 points

4. You have a family member who has been diagnosed with Lyme and/or other tick borne diseases 1 point

5. You experience  migratory muscle pain 4 points

6. You experience migratory joint pain 4 points

7. You experience tingling/burning/ numbness that migrates and/or comes and goes 4 points

8. You have received a prior diagnosis of chronic fatigue syndrome or fibromyalgia 3 points

9. You have received a prior diagnosis of a specific autoimmune disorder (lupus, MS, or rheumatoid arthritis), or of a nonspecific autoimmune disorder 3 points

10. You have had a positive Lyme test (IFA, ELISA, Western blot, PCR, and/or borrelia culture) 5 points

Score for Section 3 (     )

Section 4: Overall health score:

1. Thinking about your overall physical health, for how many of the past thirty days was your physical health not good?  __________Days

Award yourself the following points based on the total number of days:

0-5 days = 1 point

6-12 days = 2 points

13-20 days = 3 points

21-30 days = 4 points

2. Thinking about your overall mental health, for how many days during the past thirty days was your mental health not good? _________days

Award yourself the following points based on the total number of days:

0-5 days=1 point

6-12 days=2 points

13-20 days=3 points

21-30 days=4 points

Score for Section 4.2


Record your total scores for each section below and add them together to achieve your final score:

Section 1 Total:______

Section 2 Total:______

Section 3 Total:______

Section 4 Total:______

Final Score:______


This is a published example of Phenotype switching  which has limited the capability of Western Medicine to diagnose and treat the infections associated with Lyme disease:

Melanoma switches phenotypes to become metastatic and drug-resistant

Phenotype switching may be involved in changing the appearance of melanoma tumors by altering the number and type of protein receptors that dot the surface of the individual melanoma cells within a tumor. Identifying the phenotype that patients exhibit may help determine which patients are more likely to benefit from existing medications while also providing an opportunity to create new targeted therapies.

“We were able to demonstrate for the first time that different receptors within a single signaling pathway—in this case, the Wnt signaling pathway—can guide the phenotypic plasticity of tumor cells, and increased signaling of Wnt5A in particular can result in an increase in highly invasive tumor cells that are less sensitive to existing treatments for metastatic melanoma,” said Ashani Weeraratna, PhD, of The Wistar Institute in Philadelphia, Pennsylvania.

While melanoma accounts for less than 5% of all cases of skin cancer, it is the deadliest form of the disease, resulting in the majority of deaths related to skin cancer, according to the American Cancer Society. The 5-year survival rate for patients with metastatic melanoma is about 15% to 20%, and although new, targeted therapies designed to combat the disease based on a person’s genetics have become available in recent years, some of these drugs are not effective in many patients, and many who do respond well to the drugs often eventually become resistant to them.

Weeraratna’s team focused on Wnt5A, a Wnt signaling molecule that has been found in increased levels in metastatic melanomas. In order for Wnt5A to promote the phenotype switch from early in the tumor’s formation to the time it becomes metastatic, the tyrosine kinase receptor ROR2 is required. When ROR2 is not present, Wnt5A is unable to promote tumor metastasis. The only other member of the family that has been identified is ROR1, and this research was done to determine what role ROR1 might play in the progression of melanoma.

The researchers were able to determine that ROR1 inhibited the invasion of melanoma cells, and ROR1 was targeted for degradation by Wnt5A and ROR2. When ROR1 was silenced, the researchers observed that there was an increased rate of invasion of melanoma cells both in vitro and in vivo.

In addition to laboratory studies in cells and mice, the researchers tested their hypotheses in a small cohort of patients. They found that seven out of nine patients who demonstrated less than a 33% clinical response to vemurafenib had a positive expression of Wnt5A, and only two of the remaining 15 patients who had a 38% or greater clinical response to vemurafenib exhibited any Wnt5A expression.

Additionally, in eight patients who had undergone BRAF inhibitor therapy, the levels of Wnt5A were much lower in tumor cells prior to therapy compared to cells that were tested for Wnt5A after those same patients had relapsed. The study was published in Cancer Discovery (2013; doi:10.1158/2159-8290.CD-13-0005).

How cells change their phenotype

David Tosh & Jonathan M. W. Slack

Recent attention has focused on the remarkable ability of adult stem cells to produce differentiated cells from embryologically unrelated tissues. This phenomenon is an example of metaplasia and shows that embryological commitments can be reversed or erased under certain circumstances. In some cases, even fully differentiated cells can change their phenotype (transdifferentiation). This review examines recently discovered cases of metaplasia, and speculates on the potential molecular and cellular mechanisms that underlie the switches, and their significance to developmental biology and medicine.

How do infections change their phenotypes? Huang

Now, using time-lapse microscopy and other new techniques, Stanford bioengineering professor K.C. Huang and colleagues at Stanford and Princeton have created a forensic account detailing exactly how bacteria pull off this shape-shifting trick.

The experiments they describe in Molecular Microbiology now offer a step-by-step explanation of this curious behavior, and also shed light on one of the ways bacteria may develop antibiotic resistance.

Huang’s team experimented with E. coli, one of the bacteria that can cause food poisoning. It’s also a favorite of laboratory scientists, who have studied the organism for over 100 years.

Their experiments focused on the rigid cell wall that gives E. coli its characteristic rod-like shape.

In the wild, the cell wall exists to protect the bacterium, but it also send out signals that can alert our immune system to the presence of a potentially infectious intruder.

“A bacterial cell that’s growing is also constantly shedding parts of its cell wall, similar to how a snake sheds its skin every so often,” Huang said. “If a bacterium could get rid of its cell wall, it could effectively go undercover and avoid giving off the signals that its infected host might use to try to mount a response against this invader.”

When the rigid cell wall is dissolved, the bacterium becomes a shapeless blob called an L-form.

In the 1950s, Lederberg, who later founded the genetics department at Stanford, showed that E. coli could survive for a time as L-forms and then recover their rod-like shapes in a process called reversion.

Huang’s team created a molecular-level understanding of the process that Lederberg first observed. They used high-resolution microscopes to record time-lapse images of rod-shaped E. coli cells becoming L-form blobs and then reverting to rod-shaped again.

Follow the proteins:

E. coli’s cell wall is knitted together by proteins, a class of molecules that work together to perform many biological functions.

Using time-lapse microscopy, Stanford bioengineer K.C. Huang and colleagues reveal how bacteria lose the cell walls that define their shapes, become less visible to the immune system, then revert to original form and regain full infectious potential. Credit: Tom Abate and Vignesh Ramachandran

“It’s like an orchestra in which several proteins perform different roles required to build the cell wall,” Huang said.

But those studies focused on normal, rod-shaped E. coli. In this experiment, Huang’s team wanted to understand how MreB factored into the process by which L-forms reverted back to normal.Previous research has shown that one protein, MreB, acts like the conductor, coordinating the efforts of several other proteins.

“We had a suspicion that as the conductor of this orchestra during regular growth, MreB might also be critical for reversion,” Huang said.

Growing L-forms:

Under the tireless gaze of their time-lapse microscope, the researchers grew E. coli cells dosed with the antibiotic cefsulodin. A relative of penicillin, cefsulodin prevents E. coli from building cell walls.

The cefsulodin did not kill the E. coli, but as the cells divided and created successive generations, the bacteria lost their rod-shaped walls and became blob-like L-forms.

The bioengineers let the L-forms grow and reproduce for a few hours before flushing out the cefsulodin. All the while they kept these blobs under microscopic surveillance. As the cells continued to reproduce, the time-lapse images showed that later generations slowly regained their rod-like shape.

That experiment documented the process of reversion to standard form. But it did not prove that MreB was essential.

To demonstrate the link between the rod shape and MreB, the engineers performed a variation on this experiment.

After adding cefsulodin and letting the rod-shaped E. coli reproduce to become shapeless L-forms, they once again flushed out the antibiotic.

But this time, they added a different antibiotic that specifically suppressed MreB function.

Two hours later, the cell walls returned, as a rigid structure protecting the cell.

But this time the cells were still shaped like blobs, and eventually all of these misshapen cells died.

“What we found was very stark: MreB was critical for this reversion process to occur, and without MreB what would happen is that the cells would just expand in size without any notion of their normal shape,” Huang said.

In addition to offering fundamental insights into how cells maintain their structures, Huang said the findings could help researchers understand how some bacteria adapt to stressful environments.

Many antibiotics, including penicillin, target the cell wall. But bacteria can lose their cell walls and then later recover their shapes. This process of reversion might explain how bacteria develop resistance to bacteria and establish chronic infections. The populations that survive in L-form and revert to their original shape may not be as susceptible to the next dose of antibiotics.

“Better understanding of cell wall construction could lead to better antibiotic strategies,” Huang said. “And I’m always amazed to discover ways in which biology is programmed so robustly.”

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